Edaravone suspension for oral administration

ABSTRACT

An edaravone suspension for human oral administration includes edaravone particles, a dispersant, and water.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a continuation-in-part of U.S. applicationSer. No. 17/213,501, filed Mar. 26, 2021, which is a continuation ofU.S. application Ser. No. 16/872,741, filed May 12, 2020, now U.S. Pat.No. 10,987,341, issued Apr. 27, 2021, which a continuation of and claimsthe benefit of priority to International Application No.PCT/JP2019/043013, filed Nov. 1, 2019, which is based upon and claimsthe benefit of priority to Japanese Application No. 2018-207646, filedNov. 2, 2018. The entire contents of these applications are incorporatedherein by reference.

BACKGROUND OF THE INVENTION Field of the Invention

The present invention relates to an edaravone suspension for oraladministration, and relates to a kit for preparing the edaravonesuspension for oral administration.

Description of Background Art

Edaravone is 3-methyl-1-phenyl-2-pyrazolin-5-one (see formula below)

and has its medicinal use as an ALS (amyotrophic lateral sclerosis)therapeutic agent in addition to being a brain function normalizingagent (Japanese Patent Publication No. H5-31523 and Japanese Patent No.3758164).

ALS as one type of motor neuron disease is an intractable disease thatleads to respiratory failure from initial symptoms such as weakness inhands, movement disorders with fingers and fascicular contraction inupper limbs, through symptoms such as amyotrophia and/or muscularweakness, bulbar paralysis and fascicular contraction in muscles. ALS isdivided into upper limb, bulbar, lower limb and mixed types, dependingon a site of onset. In all of these types, as symptoms progress, asystemic muscle group is affected. Causal factors of ALS have not yetbeen sufficiently elucidated. The following hypotheses have beenproposed as main causal factors of ALS: (1) autoimmune theory(appearance of an autoantibody against a Ca channel); (2) excessiveexcitatory amino acid and/or toxication theory (an increase inextracellular glutamic acid and transport disorders of glutamic acid);(3) oxidative stress disorder theory (Cu/Zn superoxide dismutase (SOD)genetic abnormality and nerve cell damage caused by free radicals); (4)cytoskeleton disorder theory (accumulation of neurofilament in motornerve cells and appearance of inclusion bodies); and (5) deficiency ofneurotrophic factors.

The entire contents of these publications are incorporated herein byreference.

SUMMARY OF THE INVENTION

According to one aspect of the present invention, an edaravonesuspension for human oral administration includes edaravone particles, adispersant, and water.

According to another aspect of the present invention, an ALS therapeuticagent includes an edaravone suspension including edaravone particles, adispersant, and water such that the edaravone suspension has a dose of adrug product per one oral administration in a range of 1 to 20 mL, andthe dose contains edaravone in a range of 50 to 210 mg.

According to yet another aspect of the present invention, a kit forpreparing an edaravone suspension for human oral administration includesa solid composition including edaravone particles, and a dispersantsolution.

According to still another aspect of the present invention, an edaravonesuspension is formulated such that when edaravone in the edaravonesuspension is in a range of 90 to 120 mg, edaravone in a plasma exhibitsa mean Cmax in a range of 500 to 2500 ng/mL and a mean AUC_(0-∞) in arange of 1000 to 2500 h*ng/mL when the edaravone suspension is orallyadministered to a human.

According to still another aspect of the present invention, an edaravonesuspension is formulated such that when edaravone in the edaravonesuspension is in a range of 90 to 120 mg, and a crossover study isperformed such that the edaravone suspension is orally administered to ahuman and that an edaravone injection is used as a control drug product,a lower limit of a 90% confidence interval of a ratio of a Cmaxgeometric mean value with respect to the control drug product and alower limit of a 90% confidence interval of a ratio of an AUC_(0-∞)geometric mean value with respect to the control drug product bothexceed 0.8.

BRIEF DESCRIPTION OF THE DRAWINGS

A more complete appreciation of the invention and many of the attendantadvantages thereof will be readily obtained as the same becomes betterunderstood by reference to the following detailed description whenconsidered in connection with the accompanying drawings, wherein:

FIGURE is a graph showing the PK profile of unchanged edaravone inplasma at the time of administration of suspension described in Example26 and the PK profile of unchanged edaravone in plasma at the time ofadministration of the edaravone injection, where PO is the suspension,and IV is the injection.

DETAILED DESCRIPTION OF THE EMBODIMENTS

Embodiments will now be described with reference to the accompanyingdrawings, wherein like reference numerals designate corresponding oridentical elements throughout the various drawings.

In the following, edaravone suspensions for oral administration of thepresent invention and a kit for preparing an edaravone suspension fororal administration according to an embodiment of the present inventionare described in detail. All publications cited in the presentspecification are incorporated by reference in the presentspecification.

Further, in the present specification, “% (w/v)” means mass % withrespect to a volume of a suspension unless otherwise specified, and anumerical range indicated using “-” indicates a range includingnumerical values before and after “-” as minimum and maximum values,respectively.

A suspension for human oral administration according to an embodiment ofthe present invention contains edaravone particles, a dispersant andwater. As a result, the suspension reduces burden on ALS patients andcaregivers, and achieves an ALS therapeutic effect equivalent to that ofan injection.

A suspension according to an embodiment of the present invention mayfurther contain a thickening agent when necessary.

As a result, even patients with dysphagia can easily drink without arisk of aspiration, and a dispersion state of the edaravone particlescan be maintained for a longer time. Further, by containing a thickeningagent, when the suspension is administered to humans, variation in drugconcentration in blood among patients can be greatly reduced, and a morestable drug effect can be expected.

Edaravone can be synthesized by a person skilled in the art, forexample, using a method described in Japanese Patent Publication No.H5-31523.

The edaravone particles contained in a suspension according to anembodiment of the present invention are solid particles containingedaravone, and may be formed of edaravone alone or may contain othercomponents. Edaravone may be in a crystalline state or an amorphousstate.

Particle sizes of the edaravone particles in the suspension are notparticularly limited. However, from perspectives such as maintaining astable dispersed state in the suspension, rapid in-body absorption and asmooth feeling when the suspension is taken, preferably, a D50 particlesize (volume-based cumulative 50% particle size) is in a range of 10μm-100 μm, and a D90 particle size (volume-based cumulative 90% particlesize) is in a range of 50-300 μm; and, more preferably, the D50 particlesize is in a range of 20 μm-80 μm, and the D90 particle size is in arange of 100 μm-250 μm. In the present invention, the cumulative 50%particle size and the cumulative 90% particle size are volume-basedparticle sizes.

Particle size distribution of the edaravone particles in the suspensionis measured using a laser diffraction particle size distribution device(Sympatec/HELOS & CUVETTE) by dispersing a part of the suspension in adispersion medium for measurement (edaravone saturated aqueoussolution).

A concentration (blending amount) of the edaravone particles blended ina suspension according to an embodiment of the present invention can beappropriately adjusted according to an optimal dose of edaravone and anamount of the suspension provided to an ALS patient (one dose, a dailydose, a weekly dose, a 10-day dose, and the like). However, an amountthat allows a form as a suspension to be retained is appropriate. Whenthe edaravone particles are formed of only edaravone, the concentrationof the edaravone particles may be 2 mg/mL or more which is equal to orhigher than a saturation solubility of edaravone with respect to adispersion medium (for example, water), and is preferably 0.06%(w/v)-36% (w/v), more preferably 0.5% (w/v)-36% (w/v), or 0.5% (w/v)-20%(w/v), even more preferably 1% (w/v)-20% (w/v), or 1% (w/v)-10% (w/v),and most preferably 1% (w/v)-5% (w/v).

The suspension of the present invention contains a dispersant. As aresult, the edaravone particles in the suspension of the presentinvention are in a well dispersed state, and even when the edaravoneparticles have settled after a long period of time of storage, theedaravone particles can be quickly redispersed by shaking (for example,manual or mechanical shaking). A behavior of redispersion can beconfirmed visually or using a spectroscopic method (for example, using alaser diffraction particle size distribution device).

As the dispersant, any dispersant that allows the edaravone particles tobe well dispersed in water without causing the edaravone particles toform secondary agglomerates may be used. An example of such a dispersantis a dispersant exhibiting a transmission scattering light intensity of1% or more. Here, “1% or more” means a range of 1%-100%.

A dispersant exhibiting a transmission scattering light intensity of X %or more means a dispersant for which, when a transmission scatteringlight intensity (AT %) just below a surface of a liquid obtained bymixing 40 mL of a 0.1% (w/v) aqueous solution of the dispersant and 840mg of edaravone is measured, the transmission scattering light intensityis X % or more. For example, a dispersant exhibiting a transmissionscattering light intensity of 1% or more means a dispersant for which,when a transmission scattering light intensity (ΔT %) just below asurface of a liquid obtained by mixing 40 mL of a 0.1% (w/v) aqueoussolution of the dispersant and 840 mg of edaravone (D50: 37 μm, D90: 143μm) and stirring the mixture with a stirrer for 30 minutes or more ismeasured, the transmission scattering light intensity is 1% or more.Further, here, the transmission scattering light intensity means a valueobtained after 10 minutes after starting a measurement of a transmissionscattering light intensity, the measurement being performed by filling20 mL of the above liquid in a cylindrical sample bottle (innerdiameter: 25 mm×outer diameter: 27.5 mm×height: 72 mm) and by measuringthe transmission scattering light intensity at a height of 39-40 mm ofthe sample bottle using a TURBISCAN Tower (manufactured Formulaction)(25° C.).

Examples of a dispersant exhibiting a transmission scattering lightintensity of 1% or more include polyvinyl alcohol, sucrose fatty acidester, polysorbate, methylcellulose, and hypromellose.

Further, as the dispersant, a dispersant exhibiting a contact angle of80 degrees or less can also be suitably used. Here, “80 degrees or less”means a range of 0-80 degrees. A dispersant exhibiting a contact angleof 80 degrees or less means a dispersant for which, when a droplet ofedaravone saturated aqueous solution containing a 0.1% (w/v) dispersantdissolved therein is dropped on an edaravone tablet, an angle (contactangle) formed between a tangent of the droplet and a surface of theedaravone tablet is 80 degrees or less. Here, the edaravone tabletrefers to an edaravone tablet obtained by compression-molding 120 mg ofedaravone (D50: 37 D90: 143 μm) in a flat punch having a diameter of 8mm at a tableting pressure of 800 kg, and measurement of the contactangle refers to a case where the contact angle is measured using acontact angle measuring device (CAX-150 manufactured by Kyowa InterfaceScience) under the following conditions.

Syringe used: glass, 1 mL

Needle: 23 gauge

Liquid volume: 1 μL

Measurement time: after 3.1 seconds

Examples of a dispersant exhibiting a contact angle of 80 degrees orless include polyvinyl alcohol, sucrose fatty acid ester, polysorbate,hypromellose, and the like.

Specific examples of a preferred dispersant are one or more selectedfrom a group of polyvinyl alcohol, sucrose fatty acid ester,polysorbate, methylcellulose and hypromellose. Particularly preferably,the dispersant is one or two selected from a group of polyvinyl alcoholand methylcellulose, and most preferably, the dispersant is polyvinylalcohol.

As the polyvinyl alcohol, a polyvinyl alcohol is preferred that has asaponification degree of 86.5-89.0, of which a kinematic viscosity of a4% aqueous solution is in a range of 3 mm²/s-55.7 mm²/s at 20° C. inaccordance with Japanese Pharmacopeia Viscosity Measurement Method I,and that is recommended as a pharmaceutical additive. However, thepolyvinyl alcohol is not limited to this. For example, Gohsenol EG-03P,EG-05P, EG-05PW, EG-18P, EG-22P, EG-30P, EG-30PW, EG-40P, EG-40PW, andEG-48P, commercially available from Nippon Synthetic Chemical IndustryCo., Ltd., can be used.

These dispersants may each be independently used, or two or more ofthese dispersants may be used in combination.

A blending amount of the dispersant may be selected in a range thatallows the edaravone particles to be dispersed and does not adverselyaffect manufacturability, and is usually in a range of 0.001% (w/v)-1.0%(w/v), preferably 0.005% (w/v)-0.5% (w/v), and most preferably 0.01%(w/v)-0.1% (w/v).

In a suspension according to an embodiment of the present invention, inorder for the edaravone particles to maintain a well dispersed state fora long period of time, a thickening agent may be blended. By containinga thickening agent, an effect is achieved that the suspension is easilyswallowed without a risk of aspiration even for patients with dysphagiaand, when being administered to humans, variation in drug concentrationin blood among patients is greatly reduced, and a more stable drugeffect can be expected.

As the thickening agent, a pharmaceutically known thickening agent canbe used. Specifically, for example, carmellose sodium, dextrin,tragacanth powder, xanthan gum, and the like can be used. From aperspective of storage stability of edaravone, tragacanth powder andxanthan gum are preferable, and xanthan gum is most preferable.

These thickening agents may each be independently used, or two or moreof these thickening agents may be used in combination.

A larger blending amount of the thickening agent allows a dispersedstate to be maintained for a longer period of time. However, when theblending amount is too large, viscosity is strong and manufacturabilitydeteriorates, and a drug product becomes difficult to be swallowed andredispersibility of settled particles after a long period of time ofstorage also deteriorates, and thus, it is unfavorable. For example, thethickening agent is xanthan gum, the blending amount of the thickeningagent may be 0.1% (w/v)-1.2% (w/v), and preferably 0.2% (w/v)-1.0%(w/v), and most preferably 0.3% (w/v)-0.5% (w/v).

Blending a thickening agent can impart viscosity to the suspension,allows even a patient with dysphagia to easily drink the suspension, andcan prevent aspiration, and thus is favorable. In an embodiment of thepresent invention, the viscosity is evaluated by IDDSI (InternationalDysphagia Diet Standardisation Initiative) Framework Flow Test. Theentire contents of this publication are incorporated herein byreference. A suspension according to an embodiment of the presentinvention desirably imparts a viscosity of which an IDDSI level isclassified in a range of 1-3, preferably, 2. The viscosity of such asuspension may be in a range not exceeding 1750 mPa·s, preferably in arange of 50 mPa·s-1750 mPa·s, and most preferably in a range of 150mPa·s-900 mPa·s, when measured using a rotational viscometer (aBrookfield type viscometer) (Japanese Pharmacopeia Viscosity MeasurementMethod II or US Pharmacopeia Chapter 912 Method I, rotor: M2, rotationspeed: 30 rpm). The entire contents of these publications areincorporated herein by reference. Alternatively, when measured using acapillary tube viscometer (an Ubbelohde-type viscometer) (JapanesePharmacopeia Viscosity Measurement Method I or US Pharmacopeia Chapter911), the viscosity of the suspension may be in a range not exceeding1000 mPa·s, preferably 10 mPa·s-1000 mPa·s, and most preferably 40mPa·s-1000 mPa·s. The entire contents of these publications areincorporated herein by reference.

The blending amount of the thickening agent is not limited to the abovedescription, and can be adjusted as appropriate such that the aboveIDDSI level or viscosity is achieved.

Further, blending the thickening agent achieves an unexpected effectthat, when the suspension is administered to patients, variation inedaravone concentration transition in blood among the patients can beminimized, and thus, a stable drug effect can be expected for all thepatients. Further, a suspension according to an embodiment of thepresent invention also has a feature that a decrease in viscosity isextremely small even after long-term storage. For example, when storedin a closed glass container in a dark place at 5° C. for 12 months,there is substantially no decrease in viscosity. On the other hand, evenwhen stored in a closed glass container in a dark place at 25° C. for 6months, a rate of decrease in viscosity (measured according to JapanesePharmacopeia Viscosity Measurement Method I) is 20% or less.

In a suspension for oral administration according to an embodiment ofthe present invention, a sweetener can be blended for purposes ofadjusting taste of the suspension as a drug product for oraladministration and delaying settling of the edaravone particles byincreasing a solution density of the suspension. Among sweeteners, sugarcan increase a blending ratio as compared to other additives and cancontribute to increasing a solution density. Further, dissolving sugarallows a solution density to be brought close to that of the particles,and can contribute to suppressing a settling speed of the particles.

The density of the suspension is desirably close to that of theedaravone particles, and is in a range equal to or exceeding the densityof water, and is preferably in a rage of 1 g/mL-1.5 g/mL, and mostpreferably in a range of 1.05 g/mL-1.2 g/mL.

Examples of the sweetener include sugars, artificial sweeteners, andnon-sugar sweeteners. Specific examples of sugars include mannitol,sorbitol, xylitol, maltitol, erythritol, sucrose, trehalose, lactose,maltose, glucose, glycerin, and the like. Specific examples ofartificial sweeteners include sucralose, aspartame, acesulfamepotassium, saccharin, and the like. Specific examples of non-sugarsweeteners include thaumatin, stevia extract, and the like. Among these,sorbitol, xylitol, or sucrose is preferable, sorbitol, or sucrose ismore preferable, and sorbitol is most preferable.

These sweeteners may each be independently used, or two or more of thesesweeteners may be used in combination.

A blending amount of a sweetener can be adjusted as appropriate inconsideration of preference of a recipient and suppression of settlingof the particles. However, a blending amount of sorbitol is 5% (w/v)-70%(w/v), preferably 10% (w/v)-60% (w/v), and more preferably 20% (w/v)-50%(w/v).

Edaravone as a pharmaceutical ingredient has a property of beingsusceptible to oxidation by dissolved oxygen in a liquid, and thus, itis preferable to blend a stabilizer in a suspension according to anembodiment of the present invention. Examples of such a stabilizerinclude antioxidants such as sulfites, bisulfites, and pyrosulfites,cysteines, methionines, polyethylene glycol, polyoxyethylenepolyoxypropylene glycol, EDTA, and the like. Particularly preferred arestabilizers described in Japanese Patent Publication No. H7-121861. Thatis, the stabilizers are one or more antioxidants selected from sulfites,bisulfites and pyrosulfites, and stabilizers selected from cysteines.

Examples of sulphites include sodium sulfite (Na₂SO₃), potassium sulfite(K₂SO₃), and calcium sulfite (CaSO₃). Examples of bisulfites includesodium bisulfite (NaHSO₃), potassium bisulfite (KHSO₃), and ammoniumbisulfite (NH₄HSO₃). Examples of pyrosulfites include sodium pyrosulfite(Na₂S₂O₅) and potassium pyrosulfite (K₂S₂O₅). Further, examples ofcysteines include L-cysteine, DL-cysteine, N-acetylcysteine,hydrochlorides thereof, and the like. Most preferably, as anantioxidant, sodium bisulfite can be used, and as a cysteine, L-cysteinehydrochloride can be used.

An additive amount of the antioxidant is preferably 0.001% (w/v)-0.5%(w/v), and particularly preferably 0.01% (w/v)-0.2% (w/v), and anadditive amount of the cysteine is preferably 0.005% (w/v)-0.5% (w/v),and particularly preferably 0.01% (w/v)-0.2% (w/v).

Further, since oxidation of edaravone is accelerated at a pH of 2.5 orlower and at a pH of 6.0 or higher, a pH regulator is preferably blendedin a suspension according to an embodiment of the present invention. ThepH regulator can be used in an amount such that the pH of the suspensionis adjusted to a range of 2.5-6.0, and preferably to a range 3.0-4.5.Either a base or an acid can be used to adjust the pH to a desiredvalue. When it is necessary to lower the pH, an acidic pH regulator (forexample, a hydrochloric acid, a phosphoric acid, an acetic acid, acitric acid, a tartaric acid, or the like, preferably a phosphoric acid)can be used. When it is necessary to raise the pH, a basic pH regulator(for example, a sodium hydroxide, a potassium hydroxide, a calciumcarbonate, a magnesium oxide, a magnesium hydroxide, or the like,preferably a sodium hydroxide) can be used.

In a suspension according to an embodiment of the present invention,when necessary, pharmaceutically acceptable drug product additives suchas fragrances, preservatives and antifoaming agents may be furtherblended.

Fragrances of various flavors such as citrus flavors (such as orange,lemon, and grapefruit), peach, grape, vanilla, soda, and berry flavors(such as strawberry, cranberry, and blueberry) can be used. A preferredblending amount of a fragrance is, for example, 0.05% (w/v)-0.2% (w/v).

Examples of antifoaming agents include simethicone emulsions, fatty acidesters, polysorbates, ethanol, and the like. A blending amount of anantifoaming agent is, for example, 0.01% (w/v)-0.05% (w/v).

Examples of preservatives include methylparaben, ethylparaben,propylparaben, butylparaben, benzoic acid, sorbic acid, sodium benzoate,benzyl alcohol, phenylethanol, and the like. A blending amount of apreservative is, for example, 0.01% (w/v)-0.5% (w/v). However, in asuspension according to an embodiment of the present invention,surprisingly, growth of bacteria has not been observed even without apreservative, and thus, a preservative is not required.

A liquid medium (dispersion medium) used for a suspension for oraladministration according to an embodiment of the present invention ispreferably water, and may contain a pharmaceutically acceptable organicsolvent. Examples of such an organic solvent include propylene glycol(1,2-propanediol), polyethylene glycol 300, polyethylene glycol 400,ethanol, and the like.

Embodiments of preferred composition combinations in the suspension ofthe present invention are illustrated below, but are not limitedthereto.

(1) Edaravone particles, polyvinyl alcohol (dispersant), xanthan gum(thickening agent), sorbitol (sweetener), sodium bisulfite (stabilizer),L-cysteine hydrochloride (stabilizer), phosphoric acid (pH regulator),sodium hydroxide (pH regulator), simethicone emulsion (antifoamingagent), and water.

(2) Edaravone particles, polyvinyl alcohol (dispersant), tragacanthpowder (thickening agent), sorbitol (sweetener), sodium bisulfite(stabilizer), L-cysteine hydrochloride (stabilizer), phosphoric acid (pHregulator), sodium hydroxide (pH regulator), simethicone emulsion(antifoaming agent), and water.

(3) Edaravone particles, sucrose fatty acid ester (dispersant), xanthangum (thickening agent), sucrose (sweetener), sodium bisulfite(stabilizer), L-cysteine hydrochloride (stabilizer), acetic acid (pHregulator), sodium hydroxide (pH regulator), simethicone emulsion(antifoaming agent), and water.

(4) Edaravone particles, polyvinyl alcohol (dispersant), xanthan gum(thickening agent), sorbitol (sweetener), sodium bisulfite (stabilizer),phosphoric acid (pH regulator), sodium hydroxide (pH regulator),simethicone emulsion (antifoaming agent), and water.

(5) Edaravone particles, polyvinyl alcohol (dispersant), xanthan gum(thickening agent), sorbitol (sweetener), sodium bisulfite (stabilizer),L-cysteine hydrochloride (stabilizer), phosphoric acid (pH regulator),sodium hydroxide (pH regulator), simethicone emulsion (antifoam),fragrance, and water.

In a suspension according to an embodiment of the present invention, theedaravone particles maintain a well dispersed state for a long period oftime. Therefore, even when a certain amount is dispensed from the wholesolution, uniformity of drug content can be ensured. Further, asuspension according to an embodiment of the present invention hasfeatures such as the following: even when the edaravone particles havesettled after a long period of time of storage, the edaravone particlescan be redispersed quickly by shaking; chemical stability of edaravoneis not impaired during such a long period of time of storage; and thereis no growth of bacteria even without a preservative.

Further, in a drug product according to an embodiment of the presentinvention, by further blending a thickening agent, an effect is alsoachieved that the drug product is imparted with a moderate viscosity andthus can be easily taken even by a patient with dysphagia and a risk ofaspiration is reduced, and, when the drug product is administered tohumans, variation in drug concentration in blood among the patients isreduced, and a stable drug effect can be expected.

The suspension of the present invention exhibits excellentbioavailability. Therefore, a drug concentration transition in bloodequivalent to that in a case where an edaravone injection currently usedas an ALS therapeutic agent in a clinical setting, for example,“Radicut” (registered trademark) of a Japanese brand name, wasadministered (60 mg as edaravone was intravenously injected over 1 hour)can be reached at a very low edaravone dose as an oral dose,specifically, 90-120 mg, more specifically 100-110 mg, and mostspecifically 105 mg.

Specifically, with respect to a suspension according to an embodiment ofthe present invention, when a crossover study is performed in a humanusing an edaravone injection as a control, a lower limit of a 90%confidence interval of a ratio of a Cmax geometric mean value withrespect to the control drug product and a lower limit of a 90%confidence interval of a ratio of an AUC_(0-∞) geometric mean value withrespect to the control drug product both exceed 0.8. In the above, anoral dose of a suspension according to an embodiment of the present asedaravone is 90-120 mg, preferably 100-110 mg, and most preferably 105mg, and an edaravone injection as the control drug product containing 60mg of edaravone is injected intravenously over 1 hour. Further, in theabove study, of a suspension according to an embodiment of the presentinvention, the lower limit of the 90% confidence interval of the ratioof the Cmax geometric mean value with respect to the control drugproduct exceeds 0.8, and the 90% confidence interval of the ratio of theAUC_(0-∞) geometric mean value with respect to the control drug productcan be in a range of 0.8-1.25.

Further, in the above study, of a suspension according to an embodimentof the present invention, the 90% confidence interval of the ratio ofthe Cmax geometric mean value with respect to the control drug productis in a range of 0.8-2.0, and the 90% confidence interval of the ratioof the AUC_(0-∞) geometric mean value with respect to the control drugproduct can be in a range of 0.8-1.25.

Further, in the above, of a suspension according to an embodiment of thepresent invention, the 90% confidence interval of the ratio of the Cmaxgeometric mean value with respect to the control drug product is in arange of 0.8-1.5, and the 90% confidence interval of the ratio of theAUC_(0-∞) geometric mean value with respect to the control drug productcan be in a range of 0.8-1.25.

Further, in the above, of a suspension according to an embodiment of thepresent invention, both the ratio of the Cmax geometric mean value withrespect to the control drug product and the ratio of the AUC_(0-∞)geometric mean value with respect to the control drug product can be ina range of 0.8-1.25.

When a suspension according to an embodiment of the present invention(for example, 90-120 mg, more specifically 100-110 mg, and even morespecifically 105 mg as edaravone) is orally administered to humans, amean Cmax is in a range of 500-2500 ng/mL, and a mean AUC_(0-∞) is in arange of 1000-2500 h*ng/mL. In the above, more specifically, the meanCmax is in a range of 1000-2000 ng/mL, and the mean AUC_(0-∞) is in arange of 1500-2000 h*ng/mL. The mean Cmax and the mean AUC_(0-∞) mayeach be an arithmetic mean value or a geometric mean value.

Examples of a suspension equivalent to the above edaravone injectioninclude, but are not limited to, a suspension having the followingcomposition.

Edaravone particles: 2.1% (w/v)

Polyvinyl alcohol (dispersant): 0.1% (w/v)

Xanthan gum (thickening agent): 0.3% (w/v)

Sorbitol (sweetener): 40% (w/v)

Sodium bisulfite (stabilizer): 0.1% (w/v)

L-cysteine hydrochloride (stabilizer): 0.05% (w/v)

Sodium hydroxide (pH regulator): an appropriate amount

Phosphoric acid (pH regulator): an appropriate amount

Simethicone emulsion (antifoaming agent): 0.05% (w/v)

Dispersion medium: water

By orally administering 5 mL of the suspension (105 mg as edaravone),concentration transition in a plasma equivalent to that in a case wherean edaravone injection (60 mg as edaravone) is intravenously injectedover 60 minutes is obtained.

A suspension for oral administration according to an embodiment of thepresent invention can be prepared by mixing the above-describededaravone particles, dispersant and other ingredients (thickening agent,sweetener, and the like) when necessary, and water.

The edaravone particles to be used preferably have a D50 particle size(volume-based cumulative 50% particle size) of 2 μm-50 μm and a D90particle size (volume-based cumulative 90% particle size) of 100 μm-250μm. In order to prepare edaravone particles having the above-describedparticle sizes, for example, when the edaravone particles are formed ofonly edaravone, an edaravone raw powder obtained using a methoddescribed in Japanese Patent Publication No. H5-31523 or the like can beadjusted into edaravone particles having the desired particle sizesusing a pulverizer such as a jet mill, a hammer mill, a pin mill, or aball mill. The particle sizes of the edaravone particles can be measuredusing a dry method using a laser diffraction particle size distributiondevice (Sympatec/HELOS & CUVETTE).

By changing the particle sizes of the edaravone particles to be used, itis possible to change a dissolution rate of edaravone from an obtaineddrug product. Specifically, the smaller the particle sizes, the fasterthe dissolution. For example, when the edaravone particles are apulverized product of the edaravone raw powder obtained using the abovemethod, a D50 particle size is in a range of 10 μm-50 μm, a D90 particlesize is in a range of 50 μm-200 μm, and preferably the D50 particle sizeis in a range of 20 μm-40 μm and the D90 particle size in a range of 70μm-150 μm. Thereby, when a dissolution test (test solutions: FirstSolution, Second Solution, 0.05 mol/L of acetic acid and sodium acetatebuffer solution (pH 4.0), and the like; paddle rotation speed: 50 rpm-75rpm) is performed according to Japanese Pharmacopoeia, a drug producthaving an edaravone dissolution rate of 80% or more 30 minutes afterstarting the test is obtained, and thus, a prompt drug effect can beexpected.

For a suspension according to an embodiment of the present invention,after the components are blended, a homogeneous suspension can beprepared using a mixing method such as stirring, shaking, and ultrasonicirradiation.

An example of a suitable preparation method is a method in whichedaravone particles are uniformly dispersed (suspended) in water inwhich a dispersant is dissolved (a dispersant solution). This caseincludes both putting the edaravone particles into the dispersantsolution, and adding the dispersant solution to the edaravone particles.

Other components such as a thickening agent and a sweetener may be addedto the dispersant solution in advance before dispersing the edaravoneparticles, or may be added at the same time as when the eradavoneparticles are dispersed, or may be added after the edaravone particlesare dispersed. Further, the addition timing of these components may bedifferent for each of the components.

The suspension for oral administration of the present invention isprovided in a state in which the edaravone particles are suspended,which is preferable since there are few operations at the time ofadministration. However, a kit for preparation at the time of use mayalso be provided in which the edaravone particles and water areseparated. An example of such a form is a kit for preparing an edaravonesuspension that includes: (A) a solid composition containing theedaravone particles; and (B) a dispersant solution. The kit forpreparation at the time of use can be expected to have storage stabilityover a longer period of time as compared to a prepared suspension.

(A) The solid composition containing edaravone particles may containonly edaravone particles, or may be a mixture containing also othercomponents. As the edaravone particles, those used for preparing thesuspension can be used. Further, the solid composition containingedaravone particles is granulated using a known method, and may befinely granulated or granulated, or compressed and tableted.

Also in (B) the dispersant solution, not only the dispersant to be usedin the present invention, but other components such as a thickeningagent and a sweetener may be added. A health care worker can mix (A) and(B) and shake the mixture to obtain a suspension according to anembodiment of the present invention.

Further, a suspension for oral administration according to an embodimentof the present invention may be provided in a form of a solidcomposition that allows a suspension according to an embodiment of thepresent invention to be prepared at the time of use by only addingwater, that is, in a form of a solid composition that contains theedaravone particles and the dispersant. Of course, this solidcomposition may contain other ingredients used in a suspension accordingto an embodiment of the present invention such as a thickening agent anda sweetener. Further, this solid composition is granulated using a knownmethod, and may be finely granulated, or granulated, or compressed andtableted.

In this embodiment, a health care worker can mix the solid compositioncontaining the edaravone particles and the dispersant with water andshake the mixture to obtain a suspension according to an embodiment ofthe present invention.

A suspension according to an embodiment of the present invention isadministered using an intermittent administration method, which isdescribed in WO 2005/75434 and is currently used for ALS treatment usingan edaravone injection in a clinical setting, that is, an administrationmethod in which an administration period and a drug holiday period aretaken as one unit and this is repeated twice or more. When anadministration period and a drug holiday period are repeated two or moretimes, an end of this period is always a drug holiday period. However,it is not necessary to provide the last drug holiday period. That is,for example, when an administration period and a drug holiday period arerepeated two times, this is a case of “an administration period, a drugholiday period, an administration period, and a drug holiday period;however, without providing the last drug holiday period, a case of “anadministration period, a drug holiday period, and an administrationperiod” is also possible.

A drug holiday period is a period in which drug administration is notperformed continuously for 7 days or more, preferably 14 days.

An administration period can be 14 days, or 10 days out of 14 days. 10days out of 14 days mean any 10 days out of 14 consecutive days. The 10days in which drug administration is performed may be 10 consecutivedays or 10 non-consecutive days separated by one or more periods in eachof which drug administration is not performed for 1-4 days. As anadministration period, a preferred period can be selected whileobserving a condition of a patient.

More specifically, an example is a method in which an initial drugholiday period of 14 days is provided after an initial administrationperiod of 14 days, and then an administration period of 10 days out of14 days and a drug holiday period of 14 days are repeated. The number ofrepetitions of the administration period of 10 days out of 14 days andthe drug holiday period of 14 days is not particularly limited as longas the number of repetitions is 1 or more.

A daily dose in an intermittent administration period can be selected asappropriate according to an age and a condition (for example, severityof the disease) of a patient. In general, for an adult, a dose ofedaravone is 60 mg-400 mg, preferably 60 mg-300 mg, more preferably 90mg-210 mg, especially preferably 90 mg, 100 mg, 105 mg, 180 mg, 200 mgor 210 mg, even more preferably 105 mg or 210 mg, and most preferably105 mg.

Or, a suspension according to an embodiment of the present invention maybe administered to a patient daily or nearly daily during anadministration period. A daily dose can be selected as appropriateaccording to an age and a condition (for example, severity of thedisease) of a patient. In general, for an adult, a dose of edaravone is60 mg-400 mg, preferably 60 mg-300 mg, more preferably 90 mg-210 mg,especially preferably 90 mg, 100 mg, 105 mg, 180 mg, 200 mg or 210 mg,even more preferably 105 mg or 210 mg, and most preferably 105 mg. Inboth daily administration and intermittent administration, the number ofadministrations per day is not limited, and a preferred number ofadministrations per day can be selected while observing a condition ofthe patient. However, in consideration of patient's burden and the like,the number of administrations per day is preferably 3, 2 or 1, and ismore preferably 1.

Further, in the case of a suspension according to an embodiment of thepresent invention, edaravone can be contained at a high content.Therefore, a dose of a drug product containing edaravone of the abovedose can be reduced, and this is advantageous for patients withdysphagia. For example, in the case of a suspension according to anembodiment of the present invention, an ALS therapeutic agent can beprepared for which a dose of a drug product per one oral administrationis 1-20 mL and the dose contains 50-210 mg of edaravone.

Further, in addition to ALS, a suspension according to an embodiment ofthe present invention can also be used for diseases that have beenreported to involve oxidative stress, for example, neurodegenerativediseases with motor dysfunction such as Parkinson's disease andspinocerebellar degeneration; muscle diseases such as musculardystrophy; intracranial neurodegenerative diseases with cognitiveimpairment such as Alzheimer's disease; vascular disorders such ascerebral infarction; systemic inflammatory diseases such as multiplesclerosis and systemic scleroderma; and local inflammatory diseases suchas stomatitis.

EXAMPLES

Next, the present invention is described in detail using examples andtest examples. However, the present invention is not limited thereto.

Example 1

200 mg of polyvinyl alcohol (Nippon Synthetic Chemical Industry Co.,Ltd., EG-05P) was dissolved in 200 mL of water to prepare a 0.1% (w/v)polyvinyl alcohol aqueous solution. 100 mg of edaravone particles(edaravone powder, D50: 37 μm; D90: 143 μm) was dispersed in 10 mL ofthe polyvinyl alcohol aqueous solution to obtain an edaravone suspensionfor oral administration.

Example 2

200 mg of polyvinyl alcohol (Nippon Synthetic Chemistry Industry Co.,Ltd., EG-05P) was dissolved in 200 mL of water, and, in the resultingpolyvinyl alcohol aqueous solution, 1000 mg of xanthan gum (Sansho Co.,Ltd., KELTROL-CG) was further dissolved to prepare a 0.1% (w/v)polyvinyl alcohol/0.5% (w/v) xanthan gum aqueous solution. 100 mg ofedaravone particles (edaravone powder, D50: 37 μm; D90: 143 μm) wasdispersed in 10 mL of the polyvinyl alcohol/xanthan gum aqueous solutionto obtain an edaravone suspension.

Example 3

200 mg of polyvinyl alcohol (Nippon Synthetic Chemistry Industry Co.,Ltd., EG-05P) was dissolved in 200 mL of water, and, in the resultingpolyvinyl alcohol aqueous solution, 1000 mg of tragacanth powder (SuzuFunmatsu Yakuhin K.K.) was further dissolved to prepare a 0.1% (w/v)polyvinyl alcohol/0.5% (w/v) tragacanth powder aqueous solution. 100 mgof edaravone particles (edaravone powder, D50: 37 μm; D90: 143 μm) wasdispersed in 10 mL of the polyvinyl alcohol/tragacanth powder aqueoussolution to obtain an edaravone suspension.

Example 4

200 mg of methylcellulose (Shin-Etsu Chemical Co., Ltd., SM-25) wasdissolved in 200 mL of water to prepare a 0.1% (w/v) methylcelluloseaqueous solution. 100 mg of edaravone particles (edaravone powder, D50:37 μm; D90: 143 μm) was dispersed in 10 mL of the methylcelluloseaqueous solution to obtain an edaravone suspension.

Example 5

200 mg of methylcellulose (Shin-Etsu Chemical Co., Ltd., SM-25) wasdissolved in 200 mL of water, and, in the resulting methylcelluloseaqueous solution, 1000 mg of xanthan gum (Sansho Co., Ltd., KELTROL-CG)was further dissolved to prepare a 0.1% (w/v) methylcellulose/0.5% (w/v)xanthan gum aqueous solution. 100 mg of edaravone particles (edaravonepowder, D50: 37 μm; D90: 143 μm) was dispersed in 10 mL of themethylcellulose/xanthan gum aqueous solution to obtain an edaravonesuspension.

Example 6

200 mg of methylcellulose (Shin-Etsu Chemical Co., Ltd., SM-25) wasdissolved in 200 mL of water, and, in the resulting methylcelluloseaqueous solution, 1000 mg of tragacanth powder (Suzu Funmatsu YakuhinK.K.) was further dissolved to prepare a 0.1% (w/v) methylcellulose/0.5%(w/v) tragacanth powder aqueous solution. 100 mg of edaravone particles(edaravone powder, D50: 37 μm; D90: 143 μm) was dispersed in 10 mL ofthe methylcellulose/tragacanth powder aqueous solution to obtain anedaravone suspension.

Example 7

200 mg of polyvinyl alcohol (Nippon Synthetic Chemistry Industry Co.,Ltd., EG-05P) was dissolved in 200 mL of water, and, in the resultingpolyvinyl alcohol aqueous solution, 1600 mg of carmellose sodium (DaicelFineChem Ltd., CMC Daicel 1150) was further dissolved to prepare a 0.1%(w/v) polyvinyl alcohol/0.5% (w/v) carmellose sodium aqueous solution.100 mg of edaravone particles (edaravone powder, D50: 37 μm; D90: 143μm) was dispersed in 10 mL of the polyvinyl alcohol/carmellose sodiumaqueous solution to obtain an edaravone suspension.

Example 8

200 mg of polyvinyl alcohol (Nippon Synthetic Chemistry Industry Co.,Ltd., EG-05P) was dissolved in 200 mL of water, and, in the resultingpolyvinyl alcohol aqueous solution, 160 g of Dextrin (Nippon StarchChemical Co., Ltd., Akadama 3) was further dissolved to prepare a 0.1%(w/v) polyvinyl alcohol/0.5% (w/v) dextrin aqueous solution. 100 mg ofedaravone particles (edaravone powder, D50: 37 μm; D90: 143 μm) wasdispersed in 10 mL of the polyvinyl alcohol/dextrin aqueous solution toobtain an edaravone suspension.

Example 9

200 mg of methylcellulose (Shin-Etsu Chemical Co., Ltd., SM-25) wasdissolved in 200 mL of water, and, in the resulting methylcelluloseaqueous solution, 1600 mg of carmellose sodium (Daicel FineChem Ltd.,CMC Daicel 1150) was further dissolved to prepare a 0.1% (w/v)methylcellulose/0.5% (w/v) carmellose sodium aqueous solution. 100 mg ofedaravone particles (edaravone powder, D50: 37 μm; D90: 143 μm) wasdispersed in 10 mL of the methylcellulose/carmellose sodium aqueoussolution to obtain an edaravone suspension.

Example 10

200 mg of methylcellulose (Shin-Etsu Chemical Co., Ltd., SM-25) wasdissolved in 200 mL of water, and, in the resulting methylcelluloseaqueous solution, 160 g of Dextrin (Nippon Starch Chemical Co., Ltd.,Akadama 3) was further dissolved to prepare a 0.1% (w/v)methylcellulose/0.5% (w/v) dextrin aqueous solution. 100 mg of edaravoneparticles (edaravone powder, D50: 37 μm; D90: 143 μm) was dispersed in10 mL of the methylcellulose/dextrin aqueous solution to obtain anedaravone suspension.

Example 11

40 mg of polyvinyl alcohol (Nippon Synthetic Chemical Industry Co.,Ltd., EG-05P), 20 mg of simethicone emulsion (Basildon, PD30S) and 800mg of edaravone particles (edaravone powder, D50: 37 D90: 143 μm) weredissolved or dispersed in water such that a volume of the mixture became40 mL, and an edaravone suspension for oral administration was obtained.

Example 12

40 mg of polyvinyl alcohol (Nippon Synthetic Chemical Industry Co.,Ltd., EG-05P), 20 mg of simethicone emulsion (Basildon, PD30S), 80 mg ofxanthan gum (Sansho Co., Ltd., KELTROL-CG), and 800 mg of edaravoneparticles (edaravone powder, D50: 37 D90: 143 μm) were dissolved ordispersed in water such that a volume of the mixture became 40 mL, andan edaravone suspension for oral administration was obtained.

Example 13

40 mg of polyvinyl alcohol (Nippon Synthetic Chemical Industry Co.,Ltd., EG-05P), 20 mg of simethicone emulsion (Basildon, PD30S), 120 mgof xanthan gum (Sansho Co., Ltd., KELTROL-CG), and 800 mg of edaravoneparticles (edaravone powder, D50: 37 D90: 143 μm) were dissolved ordispersed in water such that a volume of the mixture became 40 mL, andan edaravone suspension for oral administration was obtained.

Example 14

40 mg of polyvinyl alcohol (Nippon Synthetic Chemical Industry Co.,Ltd., EG-05P), 20 mg of simethicone emulsion (Basildon, PD30S), 200 mgof xanthan gum (Sansho Co., Ltd., KELTROL-CG), and 800 mg of edaravoneparticles (edaravone powder, D50: 37 D90: 143 μm) were dissolved ordispersed in water such that a volume of the mixture became 40 mL, andan edaravone suspension for oral administration was obtained.

Example 15

40 mg of polyvinyl alcohol (Nippon Synthetic Chemical Industry Co.,Ltd., EG-05P), 20 mg of simethicone emulsion (Basildon, PD30S), 4 g ofD-sorbitol, 40 mg of xanthan gum (Sansho Co., Ltd., KELTROL-CG), and 800mg of edaravone particles (edaravone powder, D50: 37 D90: 143 μm) weredissolved or dispersed in water such that a volume of the mixture became40 mL, and an edaravone suspension for oral administration was obtained.

Example 16

40 mg of polyvinyl alcohol (Nippon Synthetic Chemical Industry Co.,Ltd., EG-05P), 20 mg of simethicone emulsion (Basildon, PD30S), 4 g ofD-sorbitol, 120 mg of xanthan gum (Sansho Co., Ltd., KELTROL-CG), and800 mg of edaravone particles (edaravone powder, D50: 37 D90: 143 μm)were dissolved or dispersed in water such that a volume of the mixturebecame 40 mL, and an edaravone suspension for oral administration wasobtained.

Example 17

40 mg of polyvinyl alcohol (Nippon Synthetic Chemical Industry Co.,Ltd., EG-05P), 20 mg of simethicone emulsion (Basildon, PD30S), 4 g ofD-sorbitol, 200 mg of xanthan gum (Sansho Co., Ltd., KELTROL-CG), and800 mg of edaravone particles (edaravone powder, D50: 37 D90: 143 μm)were dissolved or dispersed in water such that a volume of the mixturebecame 40 mL, and an edaravone suspension for oral administration wasobtained.

Example 18

40 mg of polyvinyl alcohol (Nippon Synthetic Chemical Industry Co.,Ltd., EG-05P), 40 mg of sodium bisulfite, 20 mg of L-cysteinehydrochloride hydrate, 20 mg of simethicone emulsion (Basildon, PD30S),4 g of D-sorbitol, 120 mg of xanthan gum (Sansho Co., Ltd., KELTROL-CG),and 800 mg of edaravone particles (edaravone powder, D50: 37 D90: 143μm) were dissolved or dispersed in water such that a volume of themixture became 40 mL, and into the resulting suspension, sodiumhydroxide and phosphoric acid were added in appropriate amounts toadjust a pH thereof to 4.20, and an edaravone suspension was obtained.

Example 19

40 mg of benzoic acid, 2 mg of propylparaben, and 2 mg of butylparabenwere dissolved in 40 mg of ethanol to prepare a preservative solution.40 mg of polyvinyl alcohol (Nippon Synthetic Chemical Industry Co.,Ltd., EG-05P), 40 mg of sodium bisulfite, 20 mg of L-cysteinehydrochloride hydrate, 20 mg of simethicone emulsion (Basildon, PD30S),4 g of D-sorbitol, 120 mg of xanthan gum (Sansho Co., Ltd., KELTROL-CG),and 800 mg of edaravone particles (edaravone powder, D50: 37 D90: 143μm) were dissolved or dispersed in water such that a volume of themixture became 40 mL, and after that, the preservative solution wasadded. Into the resulting suspension, sodium hydroxide and phosphoricacid were added in appropriate amounts to adjust a pH thereof to 4.20,and an edaravone suspension was obtained.

Example 20

200 mg of polyvinyl alcohol (Nippon Synthetic Chemical Industry Co.,Ltd., EG-05P) was dissolved in 200 mL of purified water to prepare a0.1% (w/v) polyvinyl alcohol solution. 120 mg of edaravone particles(edaravone powder, D50: 37 μm, D90: 143 μm) was dispersed in 10 mL ofthe polyvinyl alcohol solution to obtain an edaravone suspension.

Example 21

300 mg of edaravone particles (edaravone powder, D50: 37 μm, D90: 143μm) was dispersed in 10 mL of the 0.1% (w/v) polyvinyl alcohol solutionobtained in Example 20 to obtain an edaravone suspension.

Example 22

200 mg of polyvinyl alcohol (Nippon Synthetic Chemical Industry Co.,Ltd., EG-05P) and 1000 mg of xanthan gum (Sansho Co., Ltd., KELTROL-CG)were dissolved in 200 mL of purified water to prepare a 0.1% (w/v)polyvinyl alcohol/0.5% (w/v) xanthan gum solution. 300 mg of edaravoneparticles (edaravone powder, D50: 37 μm, D90: 143 μm) was dispersed in10 mL of the polyvinyl alcohol/xanthan gum solution to obtain anedaravone suspension.

Example 23

An edaravone suspension was obtained by using edaravone particles(edaravone powder, D50: 19 μm, D90: 73 μm) instead of the edaravoneparticles (edaravone powder, D50: 37 μm, D90: 143 μm) in Example 19.

Example 24

An edaravone suspension was obtained by using edaravone particles(edaravone powder, D50: 32 μm, D90: 110 μm) instead of the edaravoneparticles (edaravone powder, D50: 37 μm, D90: 143 μm) in Example 19.

Example 25

An edaravone suspension was obtained by using edaravone particles(edaravone powder, D50: 44 μm, D90: 204 μm) instead of the edaravoneparticles (edaravone powder, D50: 37 μm, D90: 143 μm) in Example 19.[0000]

Example 26

40 mg of polyvinyl alcohol (Nippon Synthetic Chemical Industry Co.,Ltd., EG-05P), 40 mg of sodium bisulfate, 20 mg of L-cysteinehydrochloride hydrate, 20 mg of simethicone emulsion (Basildon, PD30S),16 g of D-sorbitol, 120 mg of xanthan gum (Sansho Co., Ltd.,KELTROL-CG), and 840 mg of edaravone particles (edaravone powder, D50:37 μm, D90: 143 μm) were dissolved or dispersed in water such that avolume of the mixture became 40 mL, and into the resulting suspension,sodium hydroxide and phosphoric acid were added in appropriate amountsto adjust a pH thereof to 4.20, and an edaravone suspension wasobtained.

Example 27

An edaravone suspension was obtained by using edaravone particles(edaravone powder, D50: 17 μm, D90: 64 μm) instead of the edaravoneparticles (edaravone powder, D50: 37 μm, D90: 143 μm) in Example 26.

Example 28

An edaravone suspension was obtained by using edaravone particles(edaravone powder, D50: 21 μm, D90: 79 μm) instead of the edaravoneparticles (edaravone powder, D50: 37 μm, D90: 143 μm) in Example 26.

Example 29

An edaravone suspension was obtained by using edaravone particles(edaravone powder, D50: 31 μm, D90: 124 μm) instead of the edaravoneparticles (edaravone powder, D50: 37 μm, D90: 143 μm) in Example 26.

Example 30

An edaravone suspension was obtained by using edaravone particles(edaravone powder, D50: 46 μm, D90: 185 μm) instead of the edaravoneparticles (edaravone powder, D50: 37 μm, D90: 143 μm) in Example 26.

Example 31

An edaravone suspension was obtained by using 200 mg of tragacanthpowder (Suzu Funmatsu Yakuhin K.K.) instead of 120 mg of xanthan gum(Sansho Co., Ltd., KELTROL-CG) in Example 26.

Example 32

An edaravone suspension was obtained by using 40 mg of xanthan gum(Sansho Co., Ltd., KELTROL-CG) instead of 120 mg of xanthan gum (SanshoCo., Ltd., KELTROL-CG) in Example 26.

Example 33

An edaravone suspension was obtained by using 80 mg of xanthan gum(Sansho Co., Ltd., KELTROL-CG) instead of 120 mg of xanthan gum (SanshoCo., Ltd., KELTROL-CG) in Example 26.

Example 34

An edaravone suspension was obtained by using 160 mg of xanthan gum(Sansho Co., Ltd., KELTROL-CG) instead of 120 mg of xanthan gum (SanshoCo., Ltd., KELTROL-CG) in Example 26.

Example 35

An edaravone suspension was obtained by using 200 mg of xanthan gum(Sansho Co., Ltd., KELTROL-CG) instead of 120 mg of xanthan gum (SanshoCo., Ltd., KELTROL-CG) in Example 26.

Example 36

160 kg of D-sorbitol and 0.1 kg of simethicone emulsion (Basildon,PD30S) were dissolved and dispersed in Sterile purified water at 60° C.or above in 500 L stainless tank. After cooling to no more than 30° C.,0.4 kg of sodium bisulfite, 0.2 kg of L-cysteine hydrochloride hydratewere dissolved. Furthermore, 9.3 kg of 0.6 mol/L phosphoric acidsolution and 9.4 kg of 1 mol/L sodium hydroxide solution were added, and1.2 kg of xanthan gum (CP Kelco, KELTROL-CG) was dissolved. (Step 1) 0.4kg of Polyvinyl alcohol (Mitsubishi Chemical Corp., EG-05P) and 0.1 kgof simethicone emulsion were dissolved and dispersed in 90 L of purifiedwater at 60° C. or above in 240 L stainless tank. After cooling to nomore than 30° C., 8.4 kg of edaravone (D50: 37 μm, D90; 143 μm) wasdispersed. (Step 2) The suspension prepared in Step 2 is transferredinto the Step 1 500 L stainless tank, by vacuum transfer and mixed. Thenrinse the 240 L stainless tank using purified water and transfer rinsesolution into the 500 L stainless tank.

The pH of a suspension sampled from the mixture was measured and 0.6mol/L phosphoric acid solution was added to adjust the pH within therange of 4.1 to 4.3. Finally, Sterile purified water is added to adjustthe solution volume to 400 L, and an edaravone suspension was obtained.

Test Example 1 (Selection of Dispersant)

0.1% (w/v) aqueous solutions of drug product additives described in thefollowing table that are substances having a function capable ofdispersing solid particles in a liquid were prepared at a roomtemperature.

50 mL of each of the aqueous solutions of the additives was added to3600 mg of edaravone particles (edaravone powder, D50: 37 D90: 143 μm)and the mixture was stirred using a stirrer. The results are shown inthe following table.

TABLE 1 Appearance observation results on dispersibility No secondary Nofloating on Additive Name aggregation liquid surface Gum Arabic Powder ΔX (Kozakai Pharmaceutical Co., Ltd.) Bentonite Δ X (HOJUN Co., Ltd.,Wenger FW) Polyvinyl Alcohol ◯ ◯ (Nippon Synthetic Chemical IndustryCo., Ltd., EG-03P) Sodium Alginate X X (KIMICA Corporation, ULV-L3)Xanthan Gum X X (Sansho Co., Ltd., KELTROL-CG) Sucrose Fatty Acid ◯ ◯Ester (Mitsubishi- Chemical Foods Corporation, S-1170F) TragacanthPowder Δ X (Suzu Funmatsu Yakuhin K. K.) Methylcellulose ◯ ◯ (Shin-EtsuChemical Co., Ltd., SM-25) Hypromellose ◯ ◯ (Shin-Etsu Chemical Co.,Ltd., TC-5E) Carmellose Sodium X X (Daicel FineChem Ltd., CMC Daicel1150) ◯: There is ◯: There is no secondary no floating aggregation Δ:There is Δ: There is some floating some secondary X: There isaggregation floating X: There is secondary aggregation

From the results of the above table, it is found that only polyvinylalcohol, methylcellulose, sucrose fatty acid ester, and hypromellose cansuitably disperse edaravone particles in water.

Test Example 2 (Transmission Scattering Light Intensity Test)

0.1% (w/v) aqueous solutions of drug product additives described in thefollowing table that are substances having a function capable ofdispersing solid particles in a liquid were prepared at a roomtemperature.

40 mL of each of the aqueous solutions of the additives was added to 840mg of edaravone particles (edaravone powder, D50: 37 μm, D90: 143 μm)and the mixture was stirred using a stirrer for 30 minutes or more, anda dispersed state of the edaravone particles was confirmed.

Further, 20 mL of the dispersion liquid obtained above was filled into asample bottle (inner diameter: 25 mm×outer diameter: 27.5 mm×height: 72mm), and measurement of a transmission scattering light intensity ΔT %at a height of 39-40 mm of the sample bottle was started using aTURBISCAN Tower (manufactured by Formulaction) (with a temperature setto 25° C.), and a value obtained after 10 minutes after the start of themeasurement was defined as the transmission scattering light intensityΔT % for each additive. The transmission scattering light intensities ΔT% of the additives and the dispersion state of the edaravone particlesin the additive solutions are shown in the following table.

TABLE 2 Transmission Scattering Dispersion light Intensity State ofAdditive Name ΔT % Edaravone Polyvinyl Alcohol 32.100 dispersed (NipponSynthetic Chemical Industry Co., Ltd., EG-03P Methylcellulose 3.038dispersed (Shin-Etsu Chemical Co., Ltd., SM-15) Sucrose Fatty Acid Ester8.767 dispersed (Mitsubishi-Chemical Foods Corporation, S-1170F))Hypromellose 17.542 dispersed (Shin-Etsu Chemical Co., Ltd., TC-5E) GumArabic Powder 0.070 not (Kozakai Pharmaceutical Co., Ltd.) dispersedBentonite 0.012 not (HOJUN Co., Ltd., Wenger FW) dispersed TragacanthPowder 0.000 not (Suzu Funmatsu Yakuhin K.K.) dispersed Sodium Alginate0.012 not (KIMICA Corporation, ULV-L3) dispersed Xanthan Gum 0.007 not(Sansho Co., Ltd., KELTROL-CG dispersed Carmellose Sodium (DaicelFineChem 0.001 not Ltd., CMC Daicel 1150) dispersed Polyvinyl Alcohol15.543 dispersed (Nippon Synthetic Chemical Industry Co., Ltd., EG-050MACROGOL 6000 0.000 not dispersed D-sorbitol 0.000 not dispersedPolysorbate 80 6.151 dispersed

From the results of the above table, it can be seen that a dispersantthat can suitably disperse edaravone particles has a transmissionscattering light intensity ΔT % of 1% or more.

Test Example 3 (Contact Angle Test)

120 mg of an edaravone drug substance (D50: 37 μm, D90: 143 μm) wascompression-molded using a single-punch tableting machine (CompactionAnalyzer) (punch: flat punch having a diameter of 8 mm; tabletingpressure: 800 kgf), and an edaravone tablet for contact anglemeasurement was obtained.

Edaravone saturated aqueous solutions in which drug product additivesdescribed in the following table that are substances having a functioncapable of dispersing solid particles in a liquid were dissolved 0.1%(w/v) therein were prepared at a room temperature, and contact angleswith respect to the edaravone tablet prepared above were measured usinga contact angle measurement device (Kyowa Interface Science, Inc.,CAX-150). The results are shown in the following table.

Syringe used: glass, 1 mL

Needle: 23 gauge

Liquid volume: 1 μL

Measurement Time: after 3.1 seconds

TABLE 3 Contact Additive Name Angle Polyvinyl Alcohol 69.8 (NipponSynthetic Chemical Industry Co., Ltd., EG-03P) Sucrose Fatty Acid Ester74.3 (Mitsubishi-Chemical Foods Corporation, S-1170F) Hypromellose 78.8(Shin-Etsu Chemical Co., Ltd., TC-5E)) Gum Arabic Powder 89.5 (KozakaiPharmaceutical Co., Ltd.) Bentonite 86.9 (HOJUN Co., Ltd., Wenger FW)Tragacanth Powder 83.9 (Suzu Funmatsu Yakuhin K.K.) Sodium Alginate 86.4(KIMICA Corporation, ULV-L3) Xanthan Gum 84.0 (Sansho Co., Ltd.,KELTROL-CG) Carmellose Sodium 87.3 (Daicel FineChem Ltd., CMC Daicel1150) Polyvinyl Alcohol 79.8 (Nippon Synthetic Chemical Industry Co.,Ltd., EG-05P) D-sorbitol 83.3 Polysorbate 80 53.1

From the above results and the results of Test Example 1 or 2, it can beseen that a substance which exhibits a contact angle of 80 degrees orless for edaravone saturated aqueous solution containing 0.1% (w/v)additive with respect to the edaravone tablet can suitably disperseedaravone in water.

Test Example 4 (Stability)

5 mL of each of the edaravone suspensions prepared in Examples 1-10 wasput in a glass bottle and was sealed, and was stored at 60° C. for 4weeks. After 4 weeks, an amount of edaravone-related substances in eachsuspension was measured according to Related Substances (i) in PurityTest described in Edaravone Injection in Japanese Pharmacopeia. Theresults are shown in the following table.

TABLE 4 Example Related Substance Amount (%) 1 0.90 2 1.60 3 1.03 4 1.005 1.47 6 0.95 7 4.60 8 4.41 9 4.75 10 3.87

From the above results, it can be seen that, although an amount ofedaravone-related substances generated in any one of Examples 1-10 issmall, the amounts of the edaravone-related substances generated in thesuspensions of Examples 1-6 in which xanthan gum or tragacanth powderwas used as a thickening agent are particularly small.

Test Example 5 (Content Uniformity Test)

From each of the edaravone suspensions (40 mL each) obtained in Examples11-14, 5 mL of the suspension was sampled each time using a syringe, andthe sampling was performed 7 times in total. The edaravone content inthe 5 mL of the sampled suspension was measured. The results are shownbelow (values in the table are relative values (%) with respect to 100mg of edaravone contained in 5 mL of the original suspension).

TABLE 5 Number of Example Example Example Example sampling times 11 1213 14 First time 114.2 98.4 101.1 98.2 Second time 97.3 97.7 99.7 101.4Third time 100.2 98.8 100.6 99.6 Fourth time 89.1 101.0 100.4 100.1Fifth time 94.1 99.0 101.6 103.0 Sixth time 92.8 99.4 99.2 101.1 Seventhtime 92.5 100.9 101.5 100.3 Average 97.2 99.3 100.6 100.7

Content uniformity is ensured in all the suspensions, and particularly,a more preferable content uniformity is exhibited in the suspensions ofExamples 12-14 that each contain a thickening agent.

Test Example 6 (Redispersibility Test)

Each of the suspensions obtained in Examples 15-17 was put in acentrifugal separator and a gravity of 4000 g was applied thereto for6.6 hours, and the edaravone particles were forced to settle. Aftercompletion of the centrifugation, each of the suspensions was shakenlightly by hand. The edaravone particles in each of the suspensions ofExamples 15 and 16 were redispersed within 10 seconds, and the edaravoneparticles in the drug product of Example 17 were redispersed within 40seconds. The above gravity condition is equivalent to 3 years ofstorage.

Test Example 7 (Preservation Efficacy Test)

Preservation efficacy tests were performed according to JapanesePharmacopeia using the suspensions obtained in Examples 18-19. Althougha preservative was not blended, the suspension of Example 18 exhibited apreservative effect equivalent to that of the suspension of Example 19in which a preservative was blended.

TABLE 6 Bacterial Count (CFU/mL) Example 18 Example 19 14 days 28 days14 days 28 days Bacterial Strain Initial later later later laterPseudomonas 0.35 × 10⁶ 0 0 0 0 aeruginosa ATCC9027 Escherichia coli 0.33× 10⁶ 0 0 0 0 ATCC8739 Staphylococus 1.38 × 10⁶ 0 0 0 0 aeruginosaATCC6538 Candida albicans 0.42 × 10⁶ 0 0 0 0 ATCC10231 Aspergillus 0.64× 10⁶ 0 0 0 0 brasiliensis ATC 16404

Test Example 8

The edaravone suspensions (10 mL) obtained in Examples 20-22 were eachorally administered to 6 healthy adult males in a fasting state. Bloodsamples were collected before and 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24,36, and 48 hours after administration, and unchanged edaravoneconcentration in plasma was measured. The obtained PK profiles are shownin the following table.

TABLE 7 C_(max) AUC_(0-24 h) t_(1/2) Administered Edaravone t_(max) (h)(ng/mL) (h * ng/mL) (h) drug product dose (mg (SD) (SD) (SD) (SD)Example 20 120 0.38 1735 2241.77 5.13 (N = 6) (0.14)   (738.0) (910.63)(1.46) Example 21 300 0.75 5426 9034.06 9.05 (N = 6) (0.42) (2496)(2737.73) (3.31) Example 22 300 0.55 8805 11318.84 11.76 (N = 6) (0.25)  (933.2) (1053.43) (4.09)

Cmax and AUC_(0-24h) of Example 20 (edaravone: 120 mg) significantlyexceeded Cmax (1049 ng/mL) and AUC_(0-24h) (1374 h*ng/mL) of anedaravone injection (60 mg) described in Amyotroph Lateral SclerFrontotemporal Degener. 2017; 18 (suppl 1): 80-87. It can be seen that asuspension according to an embodiment of the present invention hasexcellent bioavailability as a drug product for oral administration.

Further, from a comparison between the PK profiles of Examples 21 and22, it can be seen that, by adding a thickening agent, variation inedaravone concentration in plasma among the subjects is reduced, thatis, a stable drug effect can be expected.

Test Example 9 (1) (Dissolution Test)

The suspensions prepared in Examples 19, 23, 24, and 25 were subjectedto dissolution tests according to Dissolution Test Method 2 (PaddleMethod) of Japanese Pharmacopoeia.

-   -   Eluate: 900 ml of the first solution (pH 1.2) or the second        solution (pH 6.8) of Dissolution Test of Japanese Pharmacopoeia    -   Measurement method: absorbance at a wavelength of 240 nm    -   Paddle rotation speed: 50 rpm    -   Number of samples: n=3

Edaravone dissolution rates 30 minutes after starting tests andsimilarities of dissolution behaviors of other examples when the drugproduct of Example 19 was used as a standard drug product weredetermined according to Bioequivalence Guidelines for generic drugs, andcalculation results of F2 functions with 15, 30, and 45 minutes asdissolution rate comparison times are shown in the following table. Itis found that a smaller the particle size of the edaravone used toprepare the edaravone suspension leads to faster dissolution, and thedissolution rate can be controlled by changing the particle size of theedaravone particles. On the other hand, from the F2 function values, inFirst Solution (pH 1.2), the drug products of Examples 23-25 exhibiteddissolution behaviors biologically equivalent to that of the drugproduct of Example 19, and, in Second Solution (pH 6.8), the drugproducts of Examples 23 and 24 exhibited dissolution behaviorsbiologically equivalent to that of the drug product of Example 19.

TABLE 8 Edaravone suspension First Solution (pH 1.2) Second Solution (pH6.8) and particle F2 function F2 function sizes of Dissolution value(deter- Dissolution value (deter- edaravone rate after 30 mination rateafter mination powder used minutes result*) 30 minutes result*) Example23 96% 96.1 95% 86.2 D50: 19 μm  (equivalent (equivalent D90: 73 μm  tostandard to standard drug drug product) product) Example 24 96% 97.4 92%95.4 D50: 32 μm  (equivalent (equivalent D90: 110 μm to standard tostandard drug drug product) product) Example 19 96% Standard 93%Standard D50: 37 μm  drug drug D90: 143 μm product product Example 2587% 56.0 74% 42.4 D50: 44 μm  (equivalent (not D90: 204 μm to standardequivalent drug to standard product) drug product) *An F2 function valueof 50 or more is equivalent to the standard drug product.

Test Example 9 (2) (Dissolution Test)

The suspensions prepared in Examples 27-30 were subjected to dissolutiontests according to Dissolution Test Method 2 (Paddle Method) of JapanesePharmacopoeia.

-   -   Eluate: 900 ml of 0.05 mol/L acetic acid/sodium acetate buffer        solution (pH 4.0) 900 ml    -   Measurement method: absorbance at a wavelength of 240 nm    -   Paddle rotation speed: 50 rpm    -   Number of samples: n=3

Edaravone dissolution rates 30 minutes after starting tests andsimilarities of dissolution behaviors of other examples when the drugproduct of Example 29 was used as a standard drug product weredetermined according to Bioequivalence Guidelines for generic drugs, andcalculation results of F2 functions with 15, 30, and 45 minutes asdissolution rate comparison times are shown in the following table. Itis found that a smaller the particle size of the edaravone used toprepare the edaravone suspension leads to faster dissolution, and thedissolution rate can be controlled by changing the particle size of theedaravone particles. On the other hand, from the F2 function values, itcan be seen that the drug products of Examples 27, 28 and 30 exhibitdissolution behaviors biologically equivalent to that of the drugproduct of Example 29.

TABLE 9 Edaravone Suspension F2 function (values in parenthesesDissolution value are particle sizes of rate after (determinationedaravone power used) 30 minutes result*) Example 27 100% 96.1 (D50: 19μm, (equivalent to standard D90: 73 μm) drug product) Example 28 100%97.4 (D50: 32 μm, (equivalent to standard D90: 110 μm) drug product)Example 29 98% Standard (D50: 37 μm, drug product D90: 143 μm) Example30 94% 56.0 (D50: 44 μm, (equivalent to standard D90: 204 μm) drugproduct) *An F2 function value of 50 or more is equivalent to thestandard drug product.

Test Example 10 (Bioequivalence Test)

The suspension obtained in Example 26 was subjected to an unblinded,single-dose, randomized crossover study in 42 Japanese healthy subjectsusing an edaravone injection as a target drug.

The administration of the edaravone suspension of Example 26 wasperformed by lightly shaking a glass bottle containing the suspension,extracting 5 mL (105 mg as edaravone) of the suspension with a syringefor oral administration, and orally administering the extractedsuspension to a subject in a fasting state.

The administration of the edaravone injection was performed byintravenously injecting 200 mL of the edaravone injection (Radicutinjection) (60 mg as edaravone) into a subject in a fasting state over 1hour.

The PK profile of unchanged edaravone in plasma at the time ofadministration of suspension described in Example 26 and PK profile ofunchanged edaravone in plasma at the time of administration of theedaravone injection are shown in FIGURE and the following table.

TABLE 10 Edaravone C_(max) AUC_(0-∞) Administered drug dose (ng/mL) (h *ng/mL) product (mg) (SD) (SD) Example 26 (po) 105 1656 1762 (N = 42) (734)  (540) Edaravone Injection  60 1253 1736 (iv) (N = 42)  (229) (331)

Further, bioequivalence evaluation results of the drug product ofExample 26 with respect the edaravone injection are shown in thefollowing table.

TABLE 11 Ratio (po/iv) 90% confidence of geometric interval of ratio ofParameter mean value geometric mean value C_(max) (ng/mL) 1.2171.090-1.359 AUC_(0-∞) (h * ng/mL) 0.977 0.917-1.041

The ratio of the geometric mean value of Cmax or AUC_(0-∞) at the timeof administration of the drug product of Example 26 with respect to theedaravone injection at the time of administration was within a range of0.8-1.25 for both Cmax and AUC_(0-∞). The 90% confidence interval of theratio of the geometric mean value was within the range of 0.8-1.25 forAUG_(0-∞). For Cmax, a lower limit of the 90% confidence interval of theratio of the geometric mean value was within the range of 0.8-1.25, butan upper limit thereof exceeded the range.

Test Example 11 (Viscosity)

Regarding the drug products described in Examples 26 and 32-35, resultsof viscosity measurement (Japanese Pharmacopeia Methods I and II andIDDSI Flow Test) are shown below.

Example Example Example Example Example 32 33 26 34 35 Viscosity 13  43 73 225 840 (Japanese mPa · s mPa · s mPa · s mPa · s mPa · sPharmacopeia Method I) *1 Viscosity 71 204 443 593 850 (Japanese mPa · smPa · s mPa · s mPa · s mPa · s Pharmacopeia Method II) *2 IDDSI FlowTest 1.2 mL 3.2 mL 6.5 mL 7.0 mL 7.2 mL (IDDSI Level) (Level (Level(Level (Level (Level 1) 2) 2) 2) 2) *1: Ubbelohde-type viscometer *2:Brookfield type viscometer, rotor: M2, rotation speed: 30 rpm

Test Example 12 (Viscosity Change)

Shown below are the viscosities of 35 mL of the drug product describedin Example 36 injected into a brown bottle having a capacity of 60 mL,which is then covered with a lid, after being stored in a dark place at5±3° C. for 3, 6, 9, and 12 months, and in a dark place at 25±2° C. for1, 3, and 6 months. The viscosities were measured according to JapanesePharmacopoeia Method I.

No decrease in viscosity was observed after storage at 5° C. for 12months, and the rate of decrease in viscosity after storage at 25° C.for 6 months was only 11.5%.

1 month 3 months 6 months 9 months 12 months Storage Condition Initiallater later later later later  5 ± 3° C. 61 mPa · s — 64 mPa · s 64 mPa· s 62 mPa · s 62 mPa · s 25 ± 2° C. 61 mPa · s 62 mPa · s 57 mPa · s 54mPa · s — —

An edaravone suspension according to an embodiment of the presentinvention is particularly useful as an ALS therapeutic agent. Therefore,the present invention has industrial applicability.

Currently, edaravone is used as an ALS therapeutic agent. However,edaravone as an ALS therapeutic agent is provided only as an injection,and an orally administered drug product is desired that is lessburdensome for patients and caregivers and is preferable from a QOLperspective.

However, unlike an injection administered directly into blood, for adrug product for oral administration for which various factors such asabsorption from the gastrointestinal tract and a first-pass effectaffect bioavailability, obtaining a drug product biologically equivalentto an injection is difficult.

As drug products for oral administration, solid drug products such astablets and capsules are common. However, for ALS patients who areexpected to have declined swallowing ability, it is difficult to takethe drug products of these forms directly. For these patients, oraladministration forms such as liquids and suspensions are desirable.

Journal of Pharmaceutical Sciences 103:730-742, 2014, InternationalJournal of Pharmaceutics 515 (2016) 490-500, and Drug Delivery, 24:1,962-978 describe CMC-Na suspensions of edaravone. However, it isdescribed that when these suspensions were administered to animals, allof them had low bioavailability.

Japanese Patent Application Laid-Open Publication No. 2004-91441describes an edaravone solution for oral administration using an aqueoussolution of tragacanth gum, and it is described that a sufficientconcentration in blood was obtained in rats. However, the concentrationin blood is lower than a result of the CMC-Na suspension described inJournal of Pharmaceutical Sciences 103:730-742, 2014, InternationalJournal of Pharmaceutics 515 (2016) 490-500, and Drug Delivery, 24:1,962-978, and a drug product described in the document does not havebioavailability comparable to that of an injection either.

To overcome low bioavailability in suspensions, InternationalPublication No. WO 2018/134243 describes an edaravone solution havingexcellent absorbability. However, due to low solubility of edaravone inwater, a dose of this solution becomes as high as 100 mL and thus is notpreferable from a perspective of medication adherence of patients. Theentire contents of these publications are incorporated herein byreference.

An edaravone suspension for oral administration according to anembodiment of the present invention can reduce burden on ALS patientsand caregivers and achieve an ALS therapeutic effect equivalent to thatof an injection.

As a result of studies, by blending a dispersant, edaravone particlescan be uniformly dispersed in water and the dispersed state can bemaintained, and, even when the edaravone particles have settled afterstorage, the edaravone particles can be quickly redispersed by lightshaking, and thus, a pharmaceutically superior edaravone suspension fororal administration can be prepared. Further, based on the findings ofJournal of Pharmaceutical Sciences 103:730-742, 2014, InternationalJournal of Pharmaceutics 515 (2016) 490-500, and Drug Delivery, 24:1,962-978, a prepared edaravone suspension for oral administration is asuspension considered to be disadvantageous from a perspective ofbioavailability based on results of previous animal experiments. Asuspension according to an embodiment of the present invention exhibitsunexpectedly superior bioavailability when being administered to humans,and thus accomplished the present invention.

According to an embodiment of the present invention, an edaravonesuspension for human oral administration contains: edaravone particles;a dispersant; and water.

In the suspension, the dispersant may be a dispersant exhibiting atransmission scattering light intensity of 1% or more.

In the suspension, the dispersant may be a dispersant exhibiting acontact angle of 80 degrees or less.

In the suspension, the dispersant may be one or two selected frompolyvinyl alcohol, methylcellulose, hypromellose, sucrose fatty acidester and polysorbate.

In the suspension, the dispersant may be one or two selected frompolyvinyl alcohol and methylcellulose.

In the suspension, the dispersant may be polyvinyl alcohol.

In the suspension, the polyvinyl alcohol may have a saponificationdegree of 86.5-89.0, and a 4% aqueous solution thereof has a kinematicviscosity of 3 mm²/s-55.7 mm²/s at 20° C.

In the suspension, a blending amount of the dispersant may be 0.001%w/v-1.0% w/v.

The suspension may further contain a thickening agent.

In the suspension, the thickening agent may be one or two selected fromxanthan gum and tragacanth powder.

In the suspension, the thickening agent may be xanthan gum.

In the suspension, a blending amount of the thickening agent may be 0.1%(w/v)-1.2% (w/v).

In the suspension, the edaravone particles in the suspension may have aD50 particle size of 10 μm-100 μm and a D90 particle size of 50 μm-300μm.

In the suspension, a blending amount of the edaravone particles may be0.06% w/v-36% w/v.

The suspension may further contain one or more additives selected from asweetener, a stabilizer and a pH regulator.

The suspension may have a viscosity of 50 mPa·s-1750 mPa·s.

The suspension may have a density of 1 g/mL-1.5 g/mL.

In the suspension, an edaravone dissolution rate 30 minutes afterstarting the test may be 80% or more, when a dissolution test (testsolution: First Solution; and paddle rotation speed: 50 rpm) isperformed according to Japanese Pharmacopeia.

According to another embodiment of the present invention, a kit forpreparing an edaravone suspension for human oral administrationcontains: (A) a solid composition containing edaravone particles; and(B) a dispersant solution.

According to yet another embodiment of the present invention, anedaravone suspension for human oral administration is characterized inthat, when the suspension containing 90-120 mg of edaravone is orallyadministered to a human, edaravone in a plasma exhibits a mean Cmax of500-2500 ng/mL and a mean AUC_(0-∞) of 1000-2500 h*ng/mL.

According to still another embodiment of the present invention, anedaravone suspension for human oral administration is characterized inthat, when a crossover study in which the suspension containing 90-120mg of edaravone is orally administered to a human is performed using anedaravone injection as a control drug product, a lower limit of a 90%confidence interval of a ratio of a Cmax geometric mean value withrespect to the control drug product and a lower limit of a 90%confidence interval of a ratio of an AUC_(0-∞) geometric mean value withrespect to the control drug product both exceed 0.8.

According to still another embodiment of the present invention, anedaravone suspension for human oral administration is characterized inthat, when a crossover study in which the suspension containing 90-120mg of edaravone is orally administered to a human is performed using anedaravone injection as a control drug product, a ratio of a Cmaxgeometric mean value with respect to the control drug product and aratio of an AUC_(0-∞) geometric mean value with respect to the controldrug product are both in a range of 0.8-1.25.

According to still another embodiment of the present invention, an ALStherapeutic agent is characterized in that a dose of a drug product perone oral administration is 1-20 mL and the dose contains 50-210 mg ofedaravone.

According to an embodiment of the present invention, an edaravonesuspension for oral administration that can reduce burden on ALSpatients and caregivers and can achieve an ALS therapeutic effectequivalent to that of an injection can be provided.

Obviously, numerous modifications and variations of the presentinvention are possible in light of the above teachings. It is thereforeto be understood that within the scope of the appended claims, theinvention may be practiced otherwise than as specifically describedherein.

What is claimed is:
 1. An edaravone suspension for human oraladministration, comprising: water; edaravone particles comprisingedaravone and dispersed in the water; a dispersant dispersing theedaravone particles in the water such that the dispersant maintains theedaravone particles in a solid particle state in the water; and athickening agent added in a blending amount such that the edaravonesuspension has IDDSI level in a range of 1 to 3, wherein a blendingamount of the edaravone particles is in a range of 0.5% (w/v) to 36%(w/v).
 2. The edaravone suspension according to claim 1, wherein thedispersant is a dispersant exhibiting a transmission scattering lightintensity of 1% or more.
 3. The edaravone suspension according to claim1, wherein the dispersant is a dispersant exhibiting a contact angle of80 degrees or less.
 4. The edaravone suspension according to claim 1,wherein the dispersant is at least one dispersant selected from thegroup consisting of polyvinyl alcohol, methylcellulose, hypromellose,sucrose fatty acid ester and polysorbate.
 5. The edaravone suspensionaccording to claim 4, wherein the dispersant is one or two dispersantsselected from the group consisting of polyvinyl alcohol andmethylcellulose.
 6. The edaravone suspension according to claim 4,wherein the dispersant is polyvinyl alcohol.
 7. The edaravone suspensionaccording to claim 4, wherein the dispersant includes the polyvinylalcohol, and the polyvinyl alcohol has a saponification degree in arange of 86.5 to 89.0, and a 4% aqueous solution of the polyvinylalcohol has a kinematic viscosity in a range of 3 mm²/s to 55.7 mm²/s at20° C. in accordance with Japanese Pharmacopeia Viscosity MeasurementMethod I.
 8. The edaravone suspension according to claim 1, wherein ablending amount of the dispersant is in a range of 0.001% (w/v) to 1.0%(w/v).
 9. The edaravone suspension according to claim 1, wherein thethickening agent is one or two thickening agents selected from the groupconsisting of xanthan gum and tragacanth powder.
 10. The edaravonesuspension according to claim 1, wherein the thickening agent is xanthangum.
 11. The edaravone suspension according to claim 1, wherein theblending amount of the thickening agent is in a range of 0.1% (w/v) to1.2% (w/v).
 12. The edaravone suspension according to claim 1, whereinthe edaravone particles in the suspension have a D50 particle size in arange of 10 μm to 100 μm and a D90 particle size of in a range of 50 μmto 300 μm.
 13. The edaravone suspension according to claim 1, wherein ablending amount of the edaravone particles is in a range of 1% (w/v) to36% (w/v).
 14. The edaravone suspension according to claim 1, furthercomprising at least one additive selected from the group consisting of asweetener, a stabilizer and a pH regulator.
 15. The edaravone suspensionaccording to claim 1 having a density of in a range of 1 g/mL to 1.5g/mL.
 16. The edaravone suspension according to claim 1, wherein thesuspension has an edaravone dissolution rate of 80% or more 30 minutesafter starting a dissolution test according to Japanese Pharmacopeia.17. The edaravone suspension according to claim 1, wherein the blendingamount of the thickening agent is such that the edaravone suspension hasIDDSI level of
 2. 18. The edaravone suspension according to claim 1having a viscosity in a range of 50 mPa·s to 1750 mPa·s in accordancewith Japanese Pharmacopeia Viscosity Measurement Method II.
 19. Theedaravone suspension according to claim 1 having a viscosity in a rangeof 10 mPa·s to 1000 mPa·s in accordance with Japanese PharmacopeiaViscosity Measurement Method I
 20. The edaravone suspension according toclaim 1, wherein a rate of decrease in viscosity of the edaravonesuspension is 20% or less in accordance with Japanese PharmacopeiaViscosity Measurement Method I, when the edaravone suspension is storedin a closed glass container in a dark place at 25° C. for 6 months. 21.The edaravone suspension according to claim 1, wherein when edaravone inthe edaravone suspension is in a range of 90 to 120 mg, edaravone in aplasma exhibits a mean Cmax in a range of 500 to 2500 ng/mL and a meanAUC_(0-∞) in a range of 1000 to 2500 h*ng/mL when the edaravonesuspension is orally administered to a human.
 22. The edaravonesuspension according to claim 1, wherein when edaravone in the edaravonesuspension is in a range of 90 to 120 mg, and a crossover study isperformed such that the edaravone suspension is orally administered to ahuman and that an edaravone injection is used as a control drug product,a lower limit of a 90% confidence interval of a ratio of a Cmaxgeometric mean value with respect to the control drug product and alower limit of a 90% confidence interval of a ratio of an AUC_(0-∞)geometric mean value with respect to the control drug product bothexceed 0.8.
 23. The edaravone suspension according to claim 1, whereinwhen edaravone in the edaravone suspension is in a range of 90 to 120mg, and a crossover study is performed such that the edaravonesuspension is orally administered to a human and that an edaravoneinjection is used as a control drug product, a ratio of a Cmax geometricmean value with respect to the control drug product and a ratio of anAUC_(0-∞) geometric mean value with respect to the control drug productare both in a range of 0.8 to 1.25.
 24. An ALS therapeutic agent,comprising: the edaravone suspension of claim 1, wherein a dose of theedaravone suspension per one oral administration is in a range of 1 to20 mL and contains the edaravone in a range of 50 to 210 mg.